Efficacy of Ceftaroline Fosamil against Escherichia coli and Klebsiella pneumoniae Strains in a Rabbit Meningitis Model

Abstract

In this study, the efficacy of ceftaroline fosamil was compared with that of cefepime in an experimental rabbit meningitis model against two Gram-negative strains (Escherichia coli QK-9 and Klebsiella pneumoniae 1173687). The penetration of ceftaroline into inflamed and uninflamed meninges was also investigated. Both regimens were bactericidal, but ceftaroline fosamil was significantly superior to cefepime against K. pneumoniae and E. coli in this experimental rabbit meningitis model (P < 0.0007 against K. pneumoniae and P < 0.0016 against E. coli). The penetration of ceftaroline was approximately 15% into inflamed meninges and approximately 3% into uninflamed meninges.A mong the less common causative agents of bacterial meningitis, Klebsiella pneumoniae, a Gram-negative microorganism, has played an increasing role in adult community-acquired or hospital-acquired meningitis in recent years (1-3). Major risk factors for K. pneumoniae meningitis are diabetes mellitus; debilitating diseases; extrameningeal K. pneumoniae infections, including bacteremia; and undergoing neurosurgical procedures (4). In Taiwan, K. pneumoniae is one of the most frequent microorganisms causing meningitis (5). Escherichia coli is the most common Gram-negative pathogen causing meningitis in the neonatal period (6).Ceftaroline fosamil, a prodrug, is rapidly converted in plasma to the microbiologically active ceftaroline, a novel cephalosporin with broad-spectrum in vitro activity against multidrug-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae, and common Gram-negative organisms (7-9). Ceftaroline fosamil, administered parenterally, is approved by the U.S. Food and Drug Administration for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Little is known about the efficacy of ceftaroline fosamil in bacterial meningitis due to Gram-negative microorganisms. The aim of this study was to test the efficacy of ceftaroline following ceftaroline fosamil administration compared with that of cefepime against K. pneumoniae and E. coli strains in an experimental rabbit meningitis model and to determine the penetration of ceftaroline into inflamed and uninflamed meninges in the rabbit. MATERIALS AND METHODS Strains.The strains used in this study, E. coli QK-9 and K. pneumoniae 1173687, were kindly provided by the Institute for Infectious Diseases, University of Bern (Bern, Switzerland). Both strains were isolated in blood cultures from patients with sepsis without meningitis from the University of Bern hospital, grown in Muller-Hinton broth, and used only after several passages in rabbits. MICs were determined by agar dilution according to NCCLS recommendations in the published literature (10). Inocula for use in rabbit infection studies were prepared from stocks stored at Ϫ80°C.Study drugs. The prodrug form of ceftaroline, ceftaroline fosamil (602 g/mg), was used for in vivo studies, and microbiologically active ceftar...

Off-label use of ceftaroline fosamil: A systematic review

“…The potential of ceftaroline for the treatment of bacterial meningitis has been explored in some animal models with apparently promising results. In the study performed by Stucki et al [30], authors have compared levels of ceftaroline and cefepime in rabbit models with inflamed meninges and in healthy subjects measuring cerebrospinal fluid (CSF) and areas under the concentration versus time curves (AUCs). Ceftaroline i.v., at the dose of 40 mg/k, has shown a penetration of CSF that was approximately 15% in inflamed meninges, while in uninflamed meninges penetration was around 3%.…”

Management of post-neurosurgical meningitis: narrative review

“…The newer lipoglycopeptides have low CNS penetration: for telavancin CNS 0.1% in non-inflamed meninges and 2% in inflamed meninges [46] and for oritavancin 2%e5% in rabbit models of meningitis [47]. The newer cephalosporins with an anti-methicillinresistant S. aureus spectrum of coverage might hold promise as their CNS penetration is similar to that of other cephalosporins: for ceftaroline 3% in non-inflamed meninges and 14%e15% in inflamed meninges [48,49], and for ceftobiprole 2% and 16%, respectively [50], both in rabbit models. Clinical data are unavailable to date.…”

Treatment strategies for central nervous system infections: an update

“…Newer cephalosporins such as ceftobiprole and ceftaroline fosamil have shown great promise in the treatment of meningitis. In experimental rabbit meningitis models, the efficacy of ceftobiprole was significantly superior to cefepime in b-lactamase-positive H. influenzae [72], while ceftaroline fosamil was significantly superior to cefepime against Klebsiella pneumoniae and E. coli [73].…”